Acylguanidine derivatives as inhibitors of bone resorption and as vitronectin receptor antagonists

ABSTRACT

The present invention relates to acylguanidine derivatives of formula (I) in which R 1 , R 2 , R 4 , R 5 , R 6 , A, m and n have the meanings indicated in the patent claims, their physiologically tolerable salts and their prodrugs. The compounds of formula (I) are valuable pharmaceutical active ingredients. They are vitronectin receptor antagonists and inhibitors of bone resorption by osteoclasts and are suitable, for example, for the therapy or prophylaxis of diseases which are caused at least partially by an undesired extend of bone resorption, for example of osteoporosis. The invention furthermore relates to processes for the preparation of compounds of formula (I), their use, in particular as pharmaceutical active ingredients, and pharmaceutical preparations comprising them.

The present invention relates to acylguanidine derivatives of theformula I,

in which R¹, R², R⁴, R⁵, R⁶, A, m and n have the meanings indicatedbelow, their physiologically tolerable salts and their prodrugs. Thecompounds of the formula I are valuable pharmaceutical active compounds.They are vitronectin receptor antagonists and inhibitors of boneresorption by osteoclasts and are suitable, for example, for the therapyand prophylaxis of diseases which are caused at least partially by anundesired extent of bone resorption, for example of osteoporosis. Theinvention furthermore relates to processes for the preparation ofcompounds of the formula I, their use, in particular as pharmaceuticalactive ingredients, and pharmaceutical preparations comprising them.

Human bones are subject to a constant dynamic renovation processcomprising bone resorption and bone formation. These processes arecontrolled by types of cell specialized for these purposes. Boneresorption is based on the destruction of bone matrix by osteoclasts.The majority of bone disorders are based on a disturbed equilibriumbetween bone formation and bone resorption.

Osteoporosis is a disease characterized by low bone mass and enhancedbone fragility resulting in an increased risk of fractures. It resultsfrom a deficit in new bone formation versus bone resorption during theongoing remodelling process.

Conventional osteoporosis treatment includes, for example, theadministration of bisphosphonates, estrogens, estrogen/progesterone(hormone replacement therapy or HRT), estrogen agonists/antagonists(selective estrogen receptor modulators or SERMs), calcitonin, vitamin Danalogues, parathyroid hormone, growth hormone secretagogues, or sodiumfluoride (Jardine et al., Annual Reports in Medicinal Chemistry 1996,31, 211).

Activated osteoclasts are polynuclear cells having a diameter of up to400 μm, which remove bone matrix Activated osteoclasts become attachedto the surface of the bone matrix and secrete proteolytic enzymes andacids into the so-called “sealing zone”, the region between their cellmembrane and the bone matrix. The acidic environment and the proteasescause the destruction of the bone. The compounds of the formula Iinhibit bone resorption by osteoclasts.

Studies have shown that the attachment of osteoclasts to the bones iscontrolled by integrin receptors on the cell surface of osteoclasts.Integrins are a superfamily of receptors which include, inter alia, thefibrinogen receptor α_(IIb)β₃ on the blood platelets and the vitronectinreceptor α_(v)β₃. The vitronectin receptor α_(v)β₃ is a membraneglycoprotein which is expressed on the cell surface of a number of cellssuch as endothelial cells, cells of the vascular smooth musculature,osteoclasts and tumor cells. The vitronectin receptor α_(IIb)β₃, whichis expressed on the osteoclast membrane, controls the process ofattachment to the bones and bone resorption and thus contributes toosteoporosis. α_(v)β₃ in this case binds to bone matrix proteins such asosteopontin, bone sialoprotein and thrombospontin, which contain thetripeptide motif Arg-Gly-Asp (or RGD).

Horton and coworkers describe RGD peptides and an anti-vitronectinreceptor antibody (23C6) Which inhibit tooth destruction by osteoclastsand the migration of osteociasts (Horton et al., Exp. Cell. Res. 1991,195, 368). In J. Cell Biol. 1990, 111, 1713, Sato et al. describeechistatin, an RGD peptide from snake venom, as a potent inhibitor ofbone resorption in a tissue culture and as an inhibitor of osteoclastadhesion to the bones. Fischer et al. (Endocrinology 1993, 132, 1411)were able to show in the rat that echistatin also inhibits boneresorption in vivo.

It was furthermore shown that the vitronectin receptor α_(v)β₃ on humancells of the vascular smooth musculature of the aorta stimulates themigration of these cells into the neointima, which finally leads toarteriosclerosis and restenosis after angioplasty (Brown et al.,Cardiovascular Res. 1994, 28, 1815). Yue et al. (Pharmacology Reviewsand Communications 1998, 10, 9-18) showed the inhibition of neointimaformation using an α_(v)β₃ antagonist.

Brooks et al. (Cell 1994, 79, 1157) showed that antibodies againstα_(v)β₃ or α_(v)β₃ antagonists can cause a shrinkage of tumors byinducing the apoptosis of blood vessel cells during angiogenesis. Thevitronectin receptor α_(v)β₃ is also involved in the progression of avariety of other types of cancer, and is overexpressed in malignantmelanoma cells (Engleman et al., Annual Reports in Medicinal Chemistry1996, 31, 191). The melanoma invasiveness correlated with thisoverexpression (Stracke et al., Encylopedia of Cancer, volume III, 1855,Academic Press, 1997; Hillis et al., Clinical Science 1996, 91, 639).Carron et al. (Cancer Res. 1998, 58, 1930) describe the inhibition oftumor growth and the inhibition of hypercalcemia of malignancy using anα_(v)β₃ antagonist.

Cheresh et al. (Science 1995, 270, 1500) describe anti-α_(Vβ) ₃antibodies or α_(v)β₃ antagonists which inhibit the bFGF-inducedangiogenesis processes in the rat eye, a property which can be usedtherapeutically in the treatment of retinopathies.

Influencing of the vitronectin receptor or of the interactions in whichit is involved thus offers the possibility of influencing differentdisease states for whose therapy and prophylaxis there continues to be aneed for suitable pharmaceutical active ingredients.

The patent application WO-A-94/12181 describes substituted aromatic ringsystems and WO-A-94/08577 describes substituted heterocycles asfibrinogen receptor antagonists and inhibitors of platelet aggregation.EP-A-528 586 and EP-A-528 587 disclose aminoalkyl-substituted orheterocyclyl-substituted phenylalanine derivatives. WO-A-95/32710discloses aryl derivatives as inhibitors of bone resorption byosteoclasts. WO-A-96/00574 describes benzodiazepines, and WO-A-96/00730describes fibrinogen receptor antagonist templates, in particularbenzodiazepines which are linked to a nitrogen-bearing 5-membered ring,as vitronectin receptor antagonists. WO-A-97/21726 describes agents forpromoting bone formation which belong to various classes of compounds,among them tyrosine derivatives containing an unsubstituted guanidinogroup. Further investigations have shown that the acylguanidines of theformula I are particularly strong inhibitors of the vitronectin receptorand of bone resorption by osteoclasts.

The present invention relates to compounds of the formula I,

in which

R¹ and R² independently of one another are hydrogen or (C₁-C₆)-alkylwhich is unsubstituted or substituted by R³, with the proviso that R¹and R² are not both hydrogen at the same time,

or in which the radicals R¹- and R²-together are a saturated orunsaturated bivalent (C₂-C₉)-alkylene radical, for example the group—(CH₂)_(p)—, in which p is 2, 3, 4, 5, 6, 7, 8 or 9, which isunsubstituted or is substituted by one or more groups from the groupconsisting of halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₆)-alkyl-, (C₅-C₁₄)-heteroaryl,(C₅-C₁₄)-heteroaryl-(C₁-C₆)-alkyl-, (C₃-C₁₂)cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₆)-alkyl- and oxo, where a 5-membered to7-membered saturated or unsaturated ring which is unsubstituted or issubstituted by R³, in particular by one or two radicals R³, and which isa carbocyclic ring or a heterocyclic ring containing one or two ringnitrogen atoms, can be fused to a carboncarbon bond in the(C₂-C₉)-alkylene radical;

R³ is (C₁-C₈)-alkyl, (C₁-C₈)-alkoxy, (C₅-C₁₄)-aryl,(C₅-C₁₄)-aryl-(C₁-C₄)-alkyl- halogen, trifluoromethyl, hydroxyl, nitroor amino;

R⁴ is hydrogen, (C₁-C₆)-alkyl-CO—O—(C₁-C₄)-alkyl- or (C₁-C₆)-alkyl,which is unsubstituted or is substituted by a radical from the groupconsisting of hydroxyl, (C₁-C₄)-alkoxy, (C₁-C₄)-alkyl-S(O)₂—,NR⁷R^(7′)and N⁺R⁷R^(7′)R^(7″)Q⁻, where R⁷, R^(7′) and R^(7′)independently of one another are hydrogen, (C₁-C₆)-alkyl, (C₅-C₁₄)-arylor (C₅-C₁₄)-aryl-(C₁-C₆)-alkyl- and Q⁻ is a physiologically tolerableanion, or in which R⁴ is one of the radicals

 in which the bonds, via which the radicals are bonded, are indicated bydashed lines;

R⁵ is (C₁-C₈)-alkyl, (C₆-C₁₄)-aryl-(C₁-₆)-alkyl- or(C₅-C₁₄)-heteroaryl-(C₁-C₅)-alkyl-, where the aryl radical or theheteroaryl radical is unsubstituted or is substituted by one, two orthree radicals R³,

R⁶ is hydrogen, (C₁-C₆)-alkyl-O—CO—, hydroxyl, (C₁-C₆)-alkyl-O—CO—O— ornitro;

A is CH₂, O, S or NH;

m is 1, 2or 3;

n is 0 or 1;

in all their stereoisomeric forms and mixtures thereof in all ratios,and their physiologically tolerable salts and their prodrugs.

All radicals which can occur more than once in the compounds of theformula I, for example the radicals R³, can in each case independentlyof one another have the meanings indicated, and they can in each case beidentical or different. Similarly, all radicals of which it is said thatthey independently of one another can have a meaning indicated, can ineach case be identical or different.

The alkyl radicals occurring in the substituents can be straight-chainor branched and can be saturated or mono-unsaturated orpoly-unsaturated. This also applies if they carry substituents or occuras substituents of other radicals, for example in alkoxy radicals,alkoxycarbonyl radicals or arylalkyl radicals. The same applies toalkylene radicals (=alkanediyl radicals). Examples of suitable(C₁-C₉)-alkyl radicals are methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, nonyl, the n-isomers of these radicals, isopropyl,isobutyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl,2,3,4-trimethylhexyl, sec-butyl, tert-butyl, tert-pentyl. Preferredalkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl and tert-butyl. The bivalent radicals correspondingto the abovementioned monovalent radicals, for example methylene,ethylene, 1,3-propylene, 1,2-propylene (=1-methylethylene), 2,3-butylene(=1,2-dimethylethylene), 1,4-butylene, 1,6-hexylene, are examples ofalkylene radicals.

Unsaturated alkyl radicals are, for example, alkenyl radicals such asvinyl, 1-propenyl, allyl, butenyl, 3-methyl-2-butenyl or alkynylradicals such as ethynyl, 1-propynyl or propargyl. Unsaturated alkyleneradicals, that is alkenylene radicals (=alkenediyl radicals) andalkynylene radicals (=alkynediyl radicals), can likewise bestraight-chain or branched. Examples of alkenylene radicals are

vinylene or propenylene, examples of alkynylene radicals are ethynyleneor propynylene.

Cycloalkyl radicals can be, for example, monocyclic, bicyclic ortricyclic. Monocyclic cycloalkyl radicals are, in particular,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl or cyclododecyl, which,however, can also be substituted by, for example, (C₁-C₄)-alkyl.Examples of substituted cycloalkyl radicals which may be mentioned are4-methylcyclohexyl and 2,3-dimethylcyclopentyl.

Halogen is, for example, fluorine, chlorine, bromine or iodine.

(C₅-C₁₄)-Aryl includes heterocyclic (C₅-C₁₄)-aryl radicals(=(C₅-C₁₄)-heteroaryl radicals) in which one or more of the 5 to 14 ringcarbon atoms are replaced by heteroatoms such as nitrogen, oxygen orsulfur, and carbocyclic (C₆-C₁₄)-aryl radicals. Examples of carbocyclic(C₅-C₁₄)-aryl radicals are phenyl, naphthyl, biphenylyl, anthryl orfluorenyl, where 1-naphthyl, 2-naphthyl and in particular phenyl arepreferred. If not stated otherwise, aryl radicals, in particular phenylradicals, can be unsubstituted or substituted by one or more radicals,preferably one, two or three radicals. In particular aryl radicals canbe substituted by identical or different radicals from the groupconsisting of (C₁-C₈)-alkyl, in particular (C₁-C₄)-alkyl,(C₁-C₈)-alkoxy, in particular (C₁-C₄)-alkoxy, halogen, such as fluorine,chlorine and bromine, nitro, amino, trifluoromethyl, hydroxyl,methylenedioxy, cyano, hydroxycarbonyl, aminocarbonyl,(C₁-C₄)-alkoxycarbonyl, phenyl, phenoxy, benzyl and benzyloxy.Generally, only up to two nitro groups can occur as substituents in thecompounds of the formula I according to the invention.

In monosubstituted phenyl radicals, the substituent can be located inthe 2-position, the 3-position or the 4-position, the 3- and the4-position being preferred. If phenyl is disubstituted, the substituentscan be in the 2,3-position, 2,4-position, 2,5-position, 2,6-position,3,4-position or 3,5-position. Preferably, in disubstituted phenylradicals, the two substituents are arranged in the 3,4-position,relative to the linkage site. In trisubstituted phenyl radicals, thesubstituents can be in the 2,3,4-position, 2,3,5-position,2,3,6-position, 2,4,5-position, 2,4,6-position or 3,4,5-position.

Beside carbocyclic systems, (C₅-(C₁₄)-aryl groups can also be monocyclicor polycyclic aromatic ring systems in which 1, 2, 3, 4 or 5 of the 5 to14 ring carbon atoms are replaced by heteroatoms, in particular byidentical or different heteroatoms from the group consisting ofnitrogen, oxygen and sulfur. Examples of heterocyclic (C₅-C₁₄)-arylgroups and (C₅-C₁₄)-heteroaryl groups are 2-pyridyl, 3-pyridyl,4-pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridyl, pyrazinyl,pyrimidinyl, indolyl, isoindolyl, indazolyl, phthalazinyl, quinolyl,isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, β-carbolinyl, orbenzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivatives ofthese radicals. The heterocyclic systems can be substituted by the samesubstituents as the abovementioned carbocyclic aryl systems.

In the series of these heteroaryl groups, monocyclic or bicyclicaromatic ring systems having 1, 2 or 3 heteroatoms, in particular having1 or 2 heteroatoms, from the group consisting of N, O, S, which can beunsubstituted or substituted by 1, 2 or 3 substituents from the groupconsisting of (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, fluorine, chlorine, nitro,amino, trifluoromethyl, hydroxyl, (C₁-C₄)-alkoxycarbonyl, phenyl,phenoxy, benzyloxy and benzyl, are preferred. Particularly preferredhere are monocyclic or bicyclic aromatic 5-membered to 1 0-membered ringsystems having 1 to 3 heteroatoms, in particular having 1 or 2heteroatoms, from the group consisting of N, O, S, which can besubstituted by 1 to 2 substituents from the group consisting of(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, phenyl, phenoxy, benzyl and benzyloxy.

If the two radicals R¹- and R²- together represent a bivalent saturatedor unsaturated (C₂-C₉)-alkylene radical, these two radicals, togetherwith the two nitrogen atoms to which they are bonded, and the centralcarbon atom of the guanidino group to which these two nitrogen atoms arebonded, form a monocyclic 1,3-diazaheterocycle which is bonded to thenitrogen atom in the group (CH₂)_(m)—CO—NH via its 2-position. Examplesof radicals of such 1,3-diazaheterocycles which can be substituted asindicated in the (C₂-C₉)-alkylene radical and also on the guanidinonitrogen atom, are the 1H-imidazol-2-yl radical, the4,5-dihydro-1H-imidazol-2-yl radical, the1,4,5,6-tetrahydro-pyrimidin-2-yl radical or the4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl radical. If a 5-membered to7-membered ring is fused to a carbon-carbon bond in the (C₂-C₉)-alkyleneradical, then the two radicals R¹ and R², together with the two nitrogenatoms to which they are bonded, and the central carbon atom of theguanidino group to which these two nitrogen atoms are bonded, form abicyclic heterocycle which is bonded to the nitrogen atom in the group(CH₂)_(m)—CO—NH and which can be substituted as indicated. The fused (orcondensed) 5-membered to 7-membered ring can be saturated,mono-unsaturated or di-unsaturated or aromatic. Thus, for example, acyclopentane ring, cyclohexane ring, cyclohexene ring, cyclohexadienering, cycloheptane ring or benzene ring can be condensed. Examples ofradicals of such bicyclic heterocycles which can be bonded to thenitrogen atom in the group (CH₂)_(m)—CO—NH are the1,3a,4,5,6,6a-hexahydro-1,3-diazapentalen-2-yl radical, the1H-benzimidazol-2-yl radical, the3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl radical, the4,5,6,7-tetrahydro-1H-benzimidazol-2-yl radical, the4,7-dihydro-1H-benzimidazol-2-yl radical or the1H-imidazo[4,5-b]pyridin-2-yl radical. If a condensed ring issubstituted and/or if the (C₂-C₅)-akylene radical is substituted, theyare preferably independently of one another monosubstituted ordisubstituted by identical or different radicals R³. If alkyl groupsrepresenting R¹ and/or R² are substituted, they are preferablyindependently of one another monosubstituted or disubstituted, inparticular monosubstituted, by identical or different radicals R³.

Optically active carbon atoms contained in the compounds of the formulaI can independently of one another have the R configuration or the Sconfiguration. The configurations on different centers can be identicalor different. The compounds of the formula I can be present in the formof pure enantiomers or pure diastereomers or in the form of enantiomermixtures, for example in the form of racemates, or of diastereomermixtures. The present invention relates to both pure enantiomers andenantiomer mixtures, for example racemates, and diastereomers anddiastereomer mixtures. The invention comprises mixtures of two or ofmore than two stereoisomers of the formula I and all ratios of thestereoisomers in the mixtures. The compounds of the formula I canoptionally be present as E isomers or Z isomers. The invention relatesto both pure E isomers and pure Z isomers and E/Z mixtures in allratios. The invention also comprises all tautomeric forms of thecompounds of the formula I. For example, beside the form shown in theformula I, also the form in which the acylguanidine units is present asa —CO—N═C(NHR¹)—NR²R⁶ group, and all other forms which differ bydifferent positions of mobile hydrogen atoms are comprised.Diastereomers, including E/Z isomers, can be separated into theindividual isomers, for example, by chromatography. Racemates can beseparated into the two enantiomers by customary methods, for example, bychromatography on chiral phases or by resolution. Stereochemicallyuniform compounds can also be obtained by employing stereochemicallyuniform starting compounds or by using stereoselective reactions.

Physiologically tolerable salts of the compounds of formula I arenontoxic, physiologically acceptable, in particular pharmaceuticallyutilizable, salts. Such salts of compounds of the formula I whichcontain acidic groups, for example carboxylic acid groups, are, forexample, alkali metal salts or alkaline earth metal salts, such as, forexample, sodium salts, potassium salts, magnesium salts and calciumsalts, and also salts with physiologically tolerable quaternary ammoniumions and acid addition salts with ammonia and physiologically tolerableorganic amines, such as, for example, triethylamine, ethanolamine ortris-2-hydroxyethyl)amine. Compounds of the formula I which containbasic groups, form acid addition salts, for example with inorganic acidssuch as hydrochloric acid, sulfuric acid or phosphoric acid, or withorganic carboxylic acids and sulfonic acids such as acetic acid, citricacid, benzoic acid, maleic acid, fumaric acid, tartaric acid,methanesulfonic acid or p-toluenesulfonic acid. Compounds of the formulaI which contain a basic group and an acidic group, for example theguanidino group and a carboxyl group, can be present as zwitterions(betaines), which are likewise included by the present invention.

The physiologically tolerable anion Q⁻, which is contained in thecompounds of the formula I when R⁴ is an alkyl radical which issubstituted by a positively charged ammonium group, is, in particular, amonovalent anion or an eqivalent of a polyvalent anion of a nontoxic,physiologically acceptable, in particular also pharmaceuticallyutilizable, inorganic or organic acid, for example the anion or an anionequivalent of one of the abovementioned acids suitable for the formationof acid addition salts. Q⁻ can thus be, for example, one of the anions(or an anion equivalent) chloride, sulfate, phosphate, acetate, citrate,benzoate, maleate, fumarate, tartrate, methanesulfonate orp-toluenesulfonate.

Salts of compounds of the formula I can be obtained by customary methodsknown to those skilled in the art, for example by combining a compoundof the formula I with an inorganic or organic acid or base in a solventor dispersant, or from other salts by cation exchange or anion exchange.The present invention also includes all salts of the compounds of theformula I which, because of low physiologically tolerability, are notdirectly suitable for use in pharmaceuticals, but are suitable, forexample, as intermediates for carrying out other chemical modificationsof the compounds of the formula I or as starting materials for thepreparation of physiologically tolerable salts.

The present invention moreover includes all solvates of compounds of theformula I, for example hydrates or adducts with alcohols, and alsoderivatives of the compounds of the formula I, for example esters andother prodrugs and other physiologically tolerable derivatives, as wellas active metabolites of the compounds of the formula I. The inventionrelates in particular to prodrugs of the compounds of the formula I,which can be converted into compounds of the formula I underphysiological conditions. Suitable prodrugs for the compounds of theformula I, i.e. chemically modified derivatives of the compounds of theformula I having properties which are improved in a desired manner, areknown to those skilled in the art. More detailed information relating toprodrugs is found, for example, in Fleisher et al., Advanced DrugDelivery Reviews 19 (1996) 115-130; Design of Prodrugs, H. Bundgaard,Ed., Elsevier, 1985; H. Bundgaard, Drugs of the Future 16 (1991) 443;Saulnier et al., Bioorg. Med. Chem. Lett. 4 (1994) 1985; Safadi et al.,Pharmaceutical Res. 10 (1993) 1350. Suitable prodrugs for the compoundsof the formula I are especially ester prodrugs, for example(C₁-C₄)-alkyl esters, of carboxylic acid groups, in particular of theCOOH group, which is present when R⁴ in the group COOR⁴ is hydrogen, andalso acyl prodrugs and carbamate prodrugs of acylatable anitrogen-containing groups such as amino groups and in particular theguanidino group. In the acyl prodrugs or carbamate prodrugs, one or moretimes, for example twice, a hydrogen atom located on a nitrogen atom inthese groups is replaced by an acyl group or carbamate group. Suitableacyl groups and carbamate groups for the acyl prodrugs and carbamateprodrugs are, for example, the groups R¹⁰—CO— and R¹¹O—CO—, in which R¹⁰is hydrogen, (C₁-C₁₈)-alkyl, (C₃-C₁₄)-cycloalkyl,(C₃-C₁₄)-cycloalkyl-(C¹-C₈)-alkyl-, (C⁵-C₁₄)-aryl, in which 1 to 5carbon atoms can be replaced by heteroatoms such as N, O, S, or(C₅-C₁₄)-aryl-(C₁-C₈)-aryl-, in which 1 to 5 carbon atoms in the arylmoiety can be replaced by heteroatoms such as N, O, S, and R¹¹ has themeanings indicated for R¹⁰ with the exception of hydrogen.

In the compounds of the formula I, the radicals R¹ and R² preferablytogether are a saturated or unsaturated, in particular a saturated,bivalent (C₂-C₅)-alkylene radical, in particular a (C₂-C₄)-alkyleneradical, especially a (C₂-C₃)-alkylene radical, which is unsubstitutedor is substituted by one or two identical or different radicals from thegroup consisting of halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₆)-alkyl-, (C₅-C₁₄)-heteroaryl,(C₅-C₁₄)-heteroaryl-(C₁-C₆)-alkyl-, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₆)-alkyl-and oxo, where a 5-membered to7-membered saturated or unsaturated ring which is unsubstituted or issubstituted by R³, in particular by one or two radicals R³, and which isa carbocyclic ring or heterocyclic ring containing one or two ringnitrogen atoms can be fused to a carboncarbon bond in the alkyleneradical. In the compounds of the formula I, the radicals R¹ and R² areparticularly preferably the group —(CH₂)_(p)—, in which p is the numbers2, 3, 4 or 5, preferably the numbers 2, 3 or 4, particularly preferablythe numbers 2 or 3, and which is unsubstituted or is substituted by oneor two identical or different radicals from the group consisting ofhalogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₆)-alkyl-, (C₅-C₁₄)-heteroaryl,(C₅-C₁₄)-heteroaryl-(C₁-C₆)-alkyl-,(C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₆)-alkyl- and oxo, where a 5-membered to7-membered saturated or unsaturated ring which is unsubstituted or issubstituted by R³, in particular by one or two radicals R³, and which isa carbocyclic ring or heterocyclic ring containing one or two ringnitrogen atoms, can be fused to a carbon-carbon bond in the group—(CH₂)_(p)—.

R³ is preferably (C₁-C₄)-alkyl or (C₁-C₄)-alkoxy.

R⁴ is preferably hydrogen or unsubstituted or substituted (C₁-C₆)-alkyl,particularly preferably hydrogen or (C₁-C₆)-alkyl, which isunsubstituted or substituted by a radical from the group consisting of(C₁-C₄)-alkoxy, (C₁-C₄)-alkyl-S(O)₂— and NR⁷R^(7′), where R⁷ and R^(7 ′)independently of one another are hydrogen or (C₁-C₄)-alkyl. R⁴ is veryparticularly preferably hydrogen or unsubstituted or substituted(C₁-C₄)-alkyl, especially preferably hydrogen or (C₁-C₄)-alkyl which isunsubstituted or substituted by a radical from the group consisting of(C₁-C₄)-alkoxy, (C₁-C₄)-alkyl-S(O)₂— and NR⁷R^(7′), where R^(7 ′) and R⁷independently of one another are hydrogen or (C₁-C₄)-alkyl.

R⁵ is preferably (C₁-C₈)-alkyl or a radical of the formula II

in which the radicals R³ can be identical or different and can belocated in any desired positions of the phenyl radical, where q is 0, 1or 2, preferably 0 or 1, particularly preferably 0. R⁵ is particularlypreferably (C₁-C₄)-alkyl or the radical of the formula II, in which q is0 or 1, very particularly preferably R⁵ is the radical of the formulaII, in which q is 0 or 1, i.e. an unsubstituted benzyl radical or abenzyl radical monosubstituted in the ortho-position, meta-position orpar-aposition by R³.

R⁶ is preferably hydrogen or (C₁-C₆)-alkyl-O—CO—, particularlypreferably hydrogen or (C₁-C₄)-alkyl-O—CO—, in particular hydrogen.

A is preferably CH₂ or O.

Preferred compounds of the formula I are those compounds in which one ormore of the radicals have preferred meanings or one specific of thepreferred meanings, all combinations of such preferred meanings being asubject of the present invention. Particularly preferred compounds ofthe formula I are those compounds in which

R¹ and R² together are a saturated or unsaturated bivalent(C₂-C₅)-alkylene radical, in particular together the group —(CH₂)_(p)—,in which p is the numbers 2, 3, 4 or 5, where the (C₂-C₅)-alkyleneradical and the group —(CH₂)_(p)— are unsubstituted or are substitutedby a radical from the group consisting of halogen, (C₁-C₆)-alkyl,(C₁-C₆)-alkoxy, (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₆)-alkyl-,(C₅-C₄)-heteroaryl, (C₅-C₁₄)-heteroaryl-(C₁-C₆)-alkyl-,(C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₆)-alkyl- and oxo, andwhere a 5-membered to 7-membered saturated or unsaturated ring which isunsubstituted or substituted by R³, in particular by one or two radicalsR³, and which is a carbocyclic ring or heterocyclic ring containing oneor two ring nitrogen atoms, can be fused to a carbon-carbon bond in the(C₂-C₅)-alkylene radical and in the group —(CH₂)_(p)—;

R³ is (C₁-C₄)-alkyl or (C₁-C₄)-alkoxy;

R⁴ is hydrogen or C₁-C₆)-alkyl which is unsubstituted or is substitutedby a radical from the group consisting of (C₁-C₄)-alkoxy,C₁-C₄)-alkyl-S(O)₂— and NR⁷R^(7′), where R⁷ and R^(7′) independently ofone another are hydrogen or C₁-C₄)-alkyl;

R⁵ is (C₁-C₈)-alkyl or a radical of the formula II

 in which q is 0 or 1 and the radical R³ can be located in any desiredposition of the phenyl radical;

R⁶ is hydrogen or (C₁-C₆)-alkyl-O—CO—;

A is CH₂ or 0;

m is 1, 2or 3;

n is 0 or 1;

in all their stereoisomeric forms and mixtures thereof in all ratios,and their physiologically tolerable salts and their prodrugs.

Very particularly preferred compounds of the formula I are thosecompounds in which

R¹ and R² together are a saturated or unsaturated bivalent(C₂-C₄)-alkylene radical, in particular together the group —(CH₂)_(p)—,in which p is the numbers 2, 3 or 4, where the (C₂-C₄)-alkylene radicaland the group —(CH₂)_(p)— are unsubstituted or are substituted by aradical from the group consisting of halogen, (C₁-C₆)-alkyl,(C₁-C₆)-alkoxy, (C₆-C₁₄)aryl, (C₆-C₄)-aryl-(C₁-C₆)-alkyl-,(C₅-C₁₄)-heteroaryl, (C₅-C₁₄)-heteroaryl-(C₁-C₆)-alkyl-,(C₃-C₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₆)-alkyl- and oxo, andwhere a 5-membered to 7-membered saturated or unsaturated ring which isunsubstituted or is substituted by R³, in particular by one or tworadicals R³, and which is a carbocyclic ring or heterocyclic ringcontaining one or two ring nitrogen atoms, can be fused to acarboncarbon bond in the (C₂-C₄)-alkylene radical and in the group—(CH₂)_(p)—;

R³ is (C₁-C₄)-alkyl or (C₁-C₄)-alkoxy;

R⁴ is hydrogen or (C₁-C₆)-alkyl;

R⁵ is (C₁-C₄)-alkyl or a radical of the formula II

 in which q is 0 or 1 and the radical R³ can be located in any desiredposition of the phenyl radical;

R⁶ is hydrogen or (C₁-C₄)-alkyl-O—CO—;

A is CH₂or O;

m is 1, 2or 3;

n is 0 or 1;

in all their stereoisomeric forms and mixtures thereof in all ratios,and their physiologically tolerable salts and their prodrugs.

Especially preferred compounds of the formula I are those in which:

R¹ and R² together are a saturated or unsaturated bivalent(C₂-C₃)-alkylene radical, in particular together the group —(CH₂)_(p)—,in which p is the numbers 2 or 3, where the (C₂-C₃)-alkylene radical andthe group —(CH₂)_(p)— are unsubstituted or are substituted by a radicalfrom the group consisting of halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,(C₆-C₁₄)-aryl, (C₆-C₄)-aryl-(C₁-C₆)-alkyl-, (C₅-C₁₄)-heteroaryl,(C₅-C₁₄)-heteroaryl-(C₁-C₆)-alkyl-, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₆)-alkyl- and oxo, and where a 5-remembered to7-membered saturated or unsaturated ring which is unsubstituted or issubstituted by R³ ₁, in particular by one or two radicals R³, and whichis a carbocyclic ring or heterocyclic ring containing one or two ringnitrogen atoms, can be fused to a carbon-carbon bond in the(C₂-C₃)-alkylene radical and in the group —(CH₂)_(p)—;

R³ is (C₁-C₄)-alkyl or (C₁-C₄)-alkoxy;

R⁴ is hydrogen or (C₁-C₄)-alkyl;

R⁵ is (C₁-C₄)-alkyl or a radical of the formula II

 in which q is 0 or 1 and the radical R³ can be located in any desiredposition of the phenyl radical;

R⁶ is hydrogen or (C₁-C₄)-alkyl-O—CO—;

A is CH₂;

m is 1;

n is 1;

in all their stereoisomeric forms and mixtures thereof in all ratios,and their physiologically tolerable salts and their prodrugs.

Especially preferred compounds of the formula I are also those in which

R¹ and R² together are a saturated or unsaturated bivalent(C₂-C₃)-alkylene radical, in particular together the group —(CH₂)_(p)—,in which p is the numbers 2 or 3, where the (C₂-C₃)-alkylene radical andthe group —(CH₂)_(p)— are unsubstituted or are substituted by a radicalfrom the group consisting of halogen, C₁-C₆)-alkyl, C₁-C₆)-alkoxy,(C₆-C₁₄)-aryl, (C₆-C₄)-aryl-(C₁-C₆)-alkyl-, (C₅-C₁₄)-heteroaryl,(C₅-C₁₄)-heteroaryl-(C₁-C₆)-alkyl-, (C₃-C₁₂)-cloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₆)-alkyl- and oxo, and where a 5-membered to7-membered saturated or unsaturated ring which is unsubstituted or issubstituted by R³, in particular by one or two radicals R³, and which isa carbocyclic ring or heterocyclic ring containing one or two ringnitrogen atoms, can be fused to a carboncarbon bond in the(C₂-C₃)-alkylene radical and in the group —(CH₂)_(p)—;

R³ is (C₁-C₄)-alkyl or (C₁-C₄)-alkoxy;

R⁴ is hydrogen or (C₁-C₄)-alkyl;

R⁵ is (C₁-C₄)-alkyl or a radical of the formula II

 in which q is 0 or 1 and the radical R³ can be located in any desiredposition of the phenyl radical;

R⁶ is hydrogen or C₁-C₄)-alkyl-O—CO—;

A is oxygen;

m is 1;

n is 1;

in all their stereoisomeric forms and mixtures thereof in all ratios,and their physiologically tolerable salts and their prodrugs.

Especially preferred compounds of the formula I are furthermore those inwhich

R¹ and R² together are a saturated or unsaturated bivalent(C₂-C₃)-alkylene radical, in particular together the group —(CH₂)_(p)—,in which p is the numbers 2 or 3, where the (C₂-C₃)-alkylene radical andthe group —(CH₂)_(p)— are unsubstituted or are substituted by a radicalfrom the group consisting of halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₆)-alkyl-, (C₅-C₁₄)-heteroaryl,(C₅-C₁₄)-heteroaryl-(C₁-C₆)-alkyl-, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₆) alkyl- and oxo, and where a 5-membered to7-membered saturated or unsaturated ring which is unsubstituted or issubstituted by R³, in particular by one or two radicals R³, and which isa carbocyclic ring or heterocyclic ring containing one or two ringnitrogen atoms, can be fused to a carboncarbon bond in the(C₂-C₃)-alkylene radical and in the group —(CH₂)_(p)—;

R³ is C₁-C₄)-alkyl or (C₁-C₄)-alkoxy;

R⁴ is hydrogen or C₁-C₄)-alkyl;

R⁵ is C₁-C₄)-alkyl or a radical of the formula II

 in which q is 0 or 1 and the radical R³ can be located in any desiredposition of the phenyl radical;

R⁶ is hydrogen or C₁-C₄)-alkyl-O—CO—;

A is oxygen;

m is 3;

n is 0;

in all their stereoisomeric forms and mixtures thereof in all ratios,and their physiologically tolerable salts and their prodrugs.

Particularly especially preferred compounds of the formula I are thosein which

R¹ and R² together are a saturated bivalent (C₂-C₃)-alkylene radicalwhich is unsubstituted, in particular together are the unsubstitutedgroup —(CH₂)₂— or the unsubstituted group —(CH₂)₃—;

R⁴ is hydrogen or (C₁-C₄)-alkyl;

R⁵ is unsubstituted benzyl;

R⁶ is hydrogen;

A is oxygen;

m is 3;

n is 0;

in all their stereoisomeric forms and mixtures thereof in all ratios,and their physiologically tolerable salts and their prodrugs.

Preferred compounds of the formula I are additionally those in which thecarbon atom to which the two groups R⁴O—CO— and R⁵OCO—NH— are bonded hasthe S configuration.

The present invention also relates to processes for the preparation ofthe compounds of the formula I. The compounds can generally be prepared,for example in the course of a convergent synthesis, by linkage of twoor more fragments which can be derived retrosynthetically from theformula I. In the preparation of the compounds of the formula I it cangenerally be advantageous or necessary in the course of the synthesis tointroduce functional groups which could lead to undesired reactions orside reactions in the respective synthesis step, in the form ofprecursors which are later converted into the desired functional groups,or temporarily to block functional groups by a protective group strategysuited to the synthesis problem, which is known to those skilled in theart (Greene and Wuts, Protective Groups in Organic Synthesis, Wiley,1991).

Thus the compounds of the formula I can be prepared, for example, bylinking in a manner known per se a carboxylic acid or carboxylic acidderivative of the

in which R⁴, R⁵, A, n and m are defined as indicated for the formula I,or alternatively functional groups can be present in the form ofprecursors which are later converted into the groups present in thecompounds of the formula I, or functional groups are present inprotected form, and in which X is a nucleophilically substitutableleaving group, with a guanidine or guanidine derivative of the formulaIV

in which R¹, R² and R⁶ are defined as indicated for the formula I, oralternatively functional groups can be present in the form of precursorswhich are later converted into the groups present in the compounds ofthe formula I, or functional groups are present in protected form.

The group COX in the formula III is preferably the carboxylic acid groupCOOH or an activated carboxylic acid derivative. X, for example, ishydroxyl or halogen, in particular chlorine or bromine, alkoxy,preferably methoxy or ethoxy, aryloxy, for example phenoxy,pentafluorophenoxy, phenylthio, methylthio, 2-pyridylthio or a radicalof a nitrogen heterocycle bonded via a nitrogen atom, in particular ofan azole, such as, for example, 1-imidazolyl. X can furthermore be, forexample, ((C₁-C₄)-alkyl)—O—CO—O— or tolylsulfonyloxy and the activatedacid derivative can thus be a mixed anhydride.

If X is hydroxyl, i.e. if the guanidine of the formula IV is reactedwith a carboxylic acid, then the carboxylic acid is expediently firstactivated. The activation can be carried out, for example, withdicyclohexylcarbodiimide (DCCl) or withO-((cyano(ethoxycarbonyl)-methylen)amino)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TOTU; König et al., Proc. 21st Europ. Peptide Symp.1990 (Eds. Giralt, Andreu), Escom, Leiden 1991, p. 143) or otheractivating reagents customary in peptide chemistry.

Beside the free guanidines of the formula IV, guanidinium salts can alsobe employed in the reaction with the compounds of the formula III, fromwhich the free guanidines are then prepared in situ or in a separatestep by means of a base. The reaction of an activated carboxylic acidderivative of the formula III with the guanidine (derivate) of theformula IV is preferably carried out in a manner known per se in aprotic or aprotic polar, but inert, organic solvent. In this case,methanol, isopropanol, tert-butanol, dimethylformamide ortetrahydrofuran at temperatures from 0° C. up to the boiling temperatureof these solvents have proven suitable, for example, in the reaction ofthe methyl esters (X=methoxy) or of the ethyl esters (X=ethoxy) with theguanidines. The reactions of compounds of the type COX with salt-freeguanidines are advantageously carried out in aprotic inert solvents suchas dimethylformamide, tetrahydrofuran, dimethoxyethane or dioxane, ifappropriate with addition of a base such as, for example, potassiumtert-butoxide or sodium methoxide. However, water can also be used as asolvent in the reaction of compounds of the formula III with guanidines,for example when using a base such as sodium hdyroxide. If X ischlorine, the reaction is advantageously carried out with addition of anacid scavenger, for example of an added base or in the presence ofexcess guanidine (derivative) for binding the resulting hydrohalic acid.The reaction mixture is worked up and, if desired, the reaction productis then purified by the customary processes familiar to those skilled inthe art.

Protective groups optionally still present in the products obtained fromthe compounds of the formulae III and IV are then removed by standardprocesses, for example tert-butyl ester groups are converted into thecarboxylic acid groups by treatment with trifluoroacetic acid, benzylgroups are removed by hydrogenation or fluorenylmethoxycarbonyl groupsare removed by secondary amines, and further reactions are carried outby standard processes, for example acylation reactions. If appropriate,conversion into physiologically tolerable salts or prodrugs can then becarried out by known processes.

The starting components of the formulae III and IV, which are linked togive the acylguanidine derivatives of the formula I, are commerciallyavailable or can be prepared by or analogously to processes described inthe literature. The preparation of the starting components of theformula III is illustrated by way of example in the following schemes,the present invention not being restricted to these syntheses or thesestarting components. It does not cause any problems to those skilled inthe art to carry out the modifications of the syntheses shown, which arenecessary for the preparation of other compounds according to theinvention.

Thus the carboxybenzaldehyde of the formula V can be reacted, forexample in the presence of pyridine and piperidine, with the malonicacid ester salt of the formula VI to give the cinnamic acid derivativeof the formula VII which, after hydrogenation, for example in thepresence of palladium on carbon, to give the compound of the formula VIIand activation of the carboxylic acid group, can be condensed with the2,3-diaminopropionic acid derivative of the formula IX to give thecompound of the formula X (Scheme 1). The condensation can be carriedout, for example, in the presence of TOTU or another customaryactivating agent for carboxylic acids. In the formula X, Z is thebenzyloxycarbonyl group, but instead of Z other groups can be present onthe nitrogen atom which either only temporarily protect the amino groupin the 2-position or which can also be present in the compounds of theformula I according to the invention and can remain in the molecule.Likewise, instead of the tert-butyl ester, other esters can be presentwhich either only temporarily protect the acid group or which can alsobe present in the compounds of the formula I according to the inventionand can remain in the molecule. Compounds analogous to the compound ofthe formula VII can also be obtained by other processes for theconversion of a carbonyl group into an alkene, for example by a Wittigreaction.

The p-hydroxybenzoic acid of the formula XI can be condensed with the2,3-diaminopropionic acid derivative of the formula IX to give thecompound of the formula XII, the above explanations applying for thecompound of the formula IX and the condensation. The compound of theformula XII can be alkylated with halocarboxylic acid derivatives understandard conditions, for example with the bromoacetic acid ester of theformula XIII to give the compound of the formula XIV (Scheme 2).p-Aminobenzoic acid and p-mercaptobenzoic acid can be reactedcorrespondingly.

The tyrosine derivative of the formula XV can be alkylated understandard conditions with halocarboxylic acid derivatives, for examplewith the bromobutyric acid ester of the formula XVI to give the compoundof the formula XVII (Scheme 3). In the formula XV, Z is thebenzyloxycarbonyl group, but instead of Z other groups can be present onthe nitrogen atom, which either only temporarily protect the amino groupor which can also be present in the compounds of the formula I accordingto the invention and can remain in the molecule. Likewise, instead ofthe tert-butyl ester, other esters can be present which either onlytemporarily protect the acid group or which can also be present in thecompounds of the formula I according to the invention and can remain inthe molecule. Analogs of the compounds of the formula XVII can beprepared correspondingly or analogously to the above preparationprocesses.

The compounds of the formulae X, XIV and XVII are examples of compoundsof the formula III in which X is methoxy or ethoxy. These compounds andanalogous compounds which are obtained from the syntheses describedabove containing a group which is an activated carboxylic acidderivative can be reacted directly with the compounds of the formula IV.The compounds obtained in the above syntheses, however, can also firstbe converted under standard conditions by cleavage of the methyl estergroup or ethyl ester group or another ester group present in theposition concerned in the compounds of the formulae X, XIV and XVII intothe corresponding carboxylic acids, which are then reacted with theguanidines of the formula IV after in situ activation, for example withTOTU or DCCl, or after conversion into an activated carboxylic acidderivative. If, as activated acid derivatives, it is intended toprepare, for example, the carboxylic acid chlorides (formula III, X=Cl),this can be carried out, for example, using thionyl chloride. If it isintended to prepare, for example, the methyl esters (X=methoxy) from thecarboxylic acids, this can be carried out by treating with gaseoushydrogen chloride in methanol. Other activated acid derivatives can beprepared in a manner known per se from the carboxylic acid chlorides ordirectly from the carboxylic acids on which they are based (X=OH), forexample the imidazolides (X=1-imidazolyl) by treating the acids withcarbonyldiimidazole (cf. Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367(1962)) or the mixed anhydrides, for example by reaction withchloroformic acid esters such as ethyl chloroformate or with tosylchloride in the presence of amines such as triethylamine in an inertsolvent. A number of suitable methods for the preparation of activatedcarboxylic acid derivatives are indicated with details of sourceliterature in J. March, Advanced Organic Chemistry, Third Edition, JohnWiley & Sons, 1985, p. 350.

The compounds of the formula I are valuable pharmaceutical activeingredients which are suitable, for example, for the therapy andprophylaxis of bone disorders, tumor diseases or cardiovasculardisorders. The compounds of the formula I and their physiologicallytolerable salts and their prodrugs can be administered to animals,preferably to mammals, and in particular to humans as pharmaceuticalsfor therapy or prophylaxis. They can be administered on their own, inmixtures with one another or in the form of pharmaceutical preparationswhich permit enteral or parenteral administration and which contain, inaddition to customary pharmaceutically innocuous carriers and/oradditives, an efficacious dose of at least one compound of the formula Iand/or its physiologically tolerable salts and/or its prodrugs as activeconstituent.

The present invention therefore also relates to the compounds of theformula I and/or their physiologically tolerable salts and/or theirprodrugs for use as pharmaceuticals, to the use of the compounds of theformula I and/or their physiologically tolerable salts and/or theirprodrugs for the production of pharmaceuticals for the therapy andprophylaxis of the diseases mentioned above or below, for example forthe therapy and prophylaxis of bone disorders or tumor diseases, andalso to the use of the compounds of the formula I and/or theirphysiologically tolerable salts and/or their prodrugs for the therapyand prophylaxis of these diseases. The present invention furthermorerelates to pharmaceutical preparations which contain an efficaciousamount of at least one compound of the formula I and/or itsphysiologically tolerable salts and/or its prodrugs together with acustomary pharmaceutically innocuous carrier.

The pharmaceuticals can be administered orally, for example in the formof pills, tablets, lacquered tablets, coated tablets, granules, hard andsoft gelatin capsules, solutions, syrups, emulsions, suspensions oraerosol mixtures. Administration, however, can also be carried outrectally, for example in the form of suppositories, or parenterally, forexample intravenously, intramuscularly or subcutaneously in the form ofinjection solutions or infusion solutions, microcapsules, implants orrods, or percutaneously or topical, for example in the form ofointments, solutions or tinctures, or in other ways, for example in theform of aerosols or nasal sprays.

The pharmaceutical preparations according to the invention are preparedin a manner known per se, one or more pharmaceutically inert inorganicand/or organic carriers being used in addition to the compound(s) of theformula I and/or its (their) physiologically tolerable salts and/or its(their) prodrugs. For the production of pills, tablets, coated tabletsand hard gelatin capsules, it is possible to use, for example, lactose,corn starch or derivatives thereof, talc, stearic acid or its salts,etc. Carriers for soft gelatin capsules and suppositories are, forexample, fats, waxes, semisolid and liquid polyols, natural or hardenedoils, etc. Suitable carriers for the production of solutions, forexample injection solutions, or of emulsions or syrups are, for example,water, alcohols, glycerol, polyols, sucrose, invert sugar, glucose,vegetable oils, etc. Suitable carriers for microcapsules, implants orrods are, for example, copolymers of glycolic acid and lactic acid. Thepharmaceutical preparations normally contain approximately 0.5 to 90% byweight of the compound(s) of the formula I and/or its (their)physiologically tolerable salts and/or its (their) prodrugs. The amountof the active ingredient(s) of the formula I and/or its (their)physiologically tolerable salts and/or its(their) prodrugs in thepharmaceutical preparations normally is 0.2 to 500 mg, preferably 1 to200 mg.

In addition to the active ingredients and carriers, the pharmaceuticalpreparations can additionally contain one or more additives, such as,for example, fillers, disintegrants, binders, lubricants, wettingagents, stabilizers, emulsifiers, preservatives, sweeteners, colorants,flavorings or aromatizers, thickeners, diluents, buffer substances, andalso solvents or solubilizers or agents for achieving a depot effect,and also salts for altering the osmotic pressure, coating agents orantioxidants. They can also contain two or more compounds of the formulaI and/or their physiologically tolerable salts and/or their prodrugs.Furthermore, in addition to at least one compound of the formula Iand/or its physiologically tolerable salts and/or its prodrugs, they canalso contain one or more other therapeutically or prophylacticallyactive ingredients.

The compounds of the formula I are antagonists of the vitronectinreceptor and have, for example, the ability to inhibit the binding ofosteoclasts to the bone surface and thereby bone resorption byosteoclasts. The action of the compounds of the formula I can bedemonstrated, for example, in an assay in which the inhibition of thebinding of vitronectin to cells which contain the vitronectin receptoris determined. Details of such an assay are given below. As vitronectinreceptor antagonists, the compounds of the formula I and theirphysiologically tolerable salts and their prodrugs are generallysuitable for the therapy and prophylaxis of diseases which are based onthe interaction between vitronectin receptors and their ligands incell-cell interaction processes or cell-matrix interaction processes, orwhich can be influenced by an inhibition of interactions of this type,or for their prevention, alleviation or cure an inhibition ofinteractions of this type is desired. As explained at the beginning,such interactions, for example, play a part in bone resorption, inangiogenesis or in the proliferation of cells of the vascular smoothmusculature. The compounds of the formula I and their physiologicallytolerable salts and their prodrugs are therefore suitable, for example,for the alleviation or cure of diseases which are caused at leastpartially by an undesired extent of bone resorption, angiogenesis orproliferation of cells of the vascular smooth musculature.

Bone diseases for whose treatment and prevention the compounds of theformula I according to the invention can be employed are especiallyosteoporosis, hypercalcemia, osteopenia, for example caused bymetastases, dental disorders, hyperparathyroidism, periarticularerosions in rheumatoid arthritis and Paget's disease. In addition, thecompounds of the formula I can be used for the allevation, avoidance ortherapy of bone disorders which are caused by a glucocorticoid, steroidor corticosteroid therapy or by a lack of sex hormone(s). All thesedisorders are characterized by bone loss, which is based on theinequilibrium between bone formation and bone destruction and which canbe favorably influenced by the inhibition of bone resorption byosteoclasts. The compounds of the formula I and/or their physiologicallytolerable salts and/or their prodrugs can also favorably be used asinhibitor of bone resorption, for example in the therapy or prophylaxisof osteoporosis, in combination with conventional osteoporosistreatments, for example in combination with bisphosphonates, estrogens,estrogen/progesterone, estrogen agonists/antagonists, calcitonin,vitamin D analogues, parathyroid hormone, growth hormone secretagogues,or sodium fluoride. Administration of the compounds of the formula Iand/or their physiologically tolerable salts and/or their prodrugs andof other active ingredients effective in the treatment or prophylaxis ofosteoporosis like those listed before can take place simultaneously orsequentially, in any order, and jointly or separately. For use in such acombination treatment or prophylaxis the compounds of the formula Iand/or their physiologically tolerable salts and/or their prodrugs andone or more other active ingredients like those listed before cantogether be present in a single pharmaceutical preparation, for exampletablets or granules, or can be present in two or more separatepharmaceutical preparations which can be contained in a single packageor in two or more separate packages. The use of the compounds of theformula I and/or their physiologically tolerable salts and/or theirprodrugs in such a combination therapy or prophylaxis and their use inthe production of pharmaceuticals for such a combination therapy orprophylaxis are also covered by the present invention. The inventionfurthermore relates to pharmaceutical preparations which compriseefficacious amounts of at least one compound of the formula I and/or itsphysiologically tolerable salts and/or its prodrugs together with atleast one other active ingredient effective in the treatment. orprophylaxis of osteoporosis or in the inhibition of bone resorption likethose listed before, together with a customary pharmaceuticallyinnocuous carrier. The above explanations on pharmaceutical preparationscorrespondingly apply to such pharmaceutical combination preparations.Apart from use as inhibitors of bone resorption by osteoclasts, thecompounds of the formula I and their physiologically tolerable salts andtheir prodrugs are used as inhibitors of tumor growth and tumormetastasis, as antiinflammatories, for the therapy or prophylaxis ofcardiovascular disorders such as arteriosclerosis or restenosis, or forthe therapy or prophylaxis of nephropathies or retinopathies, such as,for example, diabetic retinopathy. As inhibitors of tumor growth ortumor metastasis the compounds of the formula I and/or theirphysiologically tolerable salts and/or their prodrugs can also favorablybe used in combination with conventional cancer therapy. Examples ofconventional cancer therapy are given in Bertino (Editor), Encyclopediaof Cancer, Academic Press, 1997. All the above statements relating tothe use of the compounds of formula I in combination with conventionalosteoporosis therapy like, for example, possible modes of administrationand pharmaceutical combination preparations, correspondingly apply tothe use of the compounds of formula I in combination with conventionalcancer therapy.

When using the compounds of the formula I, the dose can vary within widelimits and, as is customary, is to be suited to the individualconditions in each individual case. It depends, for example, on thecompound employed which can be physiologically active by itself or canbe a prodrug that is first metabolically activated, or on the nature andseverity of the disease to be treated, or on whether an acute or chroniccondition is treated or whether prophylaxis is carried out. In the caseof oral administration, the daily dose is in general 0.01 to 100 mg/kg,preferably 0.1 to 50 mg/kg, in particular 0.1 to 5 mg/kg, for example0.3 to 0.5 mg/kg, to achieve effective results in an adult weighingabout 75 kg (in each case in mg per kg of body weight). Also in the caseof intravenous administration the daily dose is in general approximately0.01 to 100 mg/kg, preferably 0.05 to 10 mg/kg (in each case per kg ofbody weight). The daily dose can be divided, in particular in the caseof the administration of relatively large amounts, into several, forexample 2, 3 or 4, part administrations. If appropriate, depending onindividual behavior, it may be necessary to deviate upwards or downwardsfrom the daily dose indicated.

Apart from use as pharmaceutical active ingredients, the compounds ofthe formula I can also be used as vehicles or carriers of activeingredients in order to transport the active ingredient specifically tothe site of action (=drug targeting; see, for example, Targeted DrugDelivery, R. C. Juliano, Handbook of Experimental Pharmacology, Vol.100, Ed. Born, G. V. R. et al., Springer Verlag). The active ingredientsto be transported are in particular those which can be used for thetreatment of the abovementioned diseases.

The compounds of the formula I and their salts can furthermore beemployed for diagnostic purposes, for example in in vitro diagnoses ofcell or tissue samples, and as auxiliaries in biochemical investigationsin which blocking of the vitronectin receptor or influencing ofcell-cell or cell-matrix interactions is desired. They can furthermorebe used as intermediates for the preparation of other compounds, inparticular of other pharmaceutical active ingredients, which areobtainable from the compounds of the formula I, for example bymodification or introduction of substituents or functional groups.

EXAMPLES

The products were identified via mass spectra (MS) and/or NMR spectra.Compounds which were purified by chromatography using an eluent whichcontained, for example, acetic acid or trifluoroacetic acid, and werethen freeze-dried, or in which in the last synthesis step, for example,trifluoroacetic acid was employed to remove a tert-butyl protectivegroup, in some cases still contained, depending on how the freeze-dryingwas carried out, the acid originating from the eluent or the lastsynthesis step and were obtained partially or completely in the form ofa salt of the acid used, for example in the form of the acetic acid saltor trifluoroacetic acid salt.

Example 1 (2S)-2-Benzyloxycarbonylamino-3-(4-(3-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)propyloxy)phenyl)propionicAcid

a) tert-Butyl(2S)-2-Benzyloxycarbonylamino-3-(4-(3-ethoxycarbonylpropyloxy)phenyl)propionate

7.42 g (0.02 mol) of N-benzyloxycarbonyl-L-tyrosine tert-butyl esterwere refluxed for 6 h together with 9.77 g(0.03 mol) of cesium carbonateand 3.9 g (0.02 mol) of ethyl 4-bromo-butyrate in about 60 ml ofacetone. After cooling the reaction mixture, the solvent was removed invacuo. The residue was partitioned between ethyl acetate and water(1/1). After separation of the phases, the organic phase was washed twotimes each with water and saturated sodium chloride solution, dried oversodium sulfate and concentrated in vacuo. The oily crude product waspurified by flash chromatography on silica gel(dichloromethane/acetonitrile 25/1). Yield: 9.4 g (97%) of viscous oil.R_(f)=0.36 (silica gel, dichloromethane/methanol 9911).

b) tert-Butyl(2S)-2Benzyloxycarbonylamino-3-(4-(3-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)propyloxy)phenyl)propionate

6.72 g (0.06 mol) of potassium tert-butoxide were added to a solution of8.13 g (0.06 mol) of 1-amino-1,4,5,6-tetrahydropyrimidine hydrochloridein 100 ml of absolute dimethylformamide. After stirring at roomtemperature for 30 min, 7.2 g (0.015 mol) of tert-butyl(2S)-2-benzyloxycarbonylamino-3-(4-(3-ethoxycarbonylpropyloxy)phenyl)propionatewere added to this solution and it was stirred at room temperature for12 h. After removal of the solvent in vacuo, the residue was treatedwith 300 ml of ethyl acetate and 100 ml of water, and the organic phasewas separated off, washed two times with saturated sodium chloridesolution, dried over sodium sulfate and concentrated. The crude productthus obtained was immediately chromatographed on silica gel(dichloromethane/methanol/glacial acetic acid 10015/1). 5.4 g (60.6%) ofamorphous product were obtained.

c)(2S)-Benzyloxycarbonylamino-3-(4-(3-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)propyloxy)phenyl)propionicAcid 5.4 g (0.009 mol) of tert-butyl(2S)-2-benzyloxycarbonylamino-3-(4-(3-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)propyloxy)phenyl)propionateacetic acid salt were dissolved in 20 ml of trifluoroacetic acid/water(95/5) and the solution was stirred at room temperature for 30 min. Thereaction solution was then concentrated in vacuo. The residue wasdissolved in water and the solution was freeze-dried. Yield: 5.2 g(98%).

MS (ES⁺): m/e=483.3 (M+H⁺, 100%).

Example 2(2S)-2-Benzyloxycarbonylamino-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionicAcid

a) 4-(2-Methoxycarbonylvinyl)benzoic Acid 18.74 g (0.12 mol) ofmonomethyl malonate potassium salt were suspended in 18 ml of pyridine.15.01 g (0.1 mol) of 4-carboxybenzaldehyde and 0.85 g (0.01 mol) ofpiperidine were added at room temperature with stirring. The mixture wasrefluxed until the evolution of CO₂ was complete (about 2 h), then afurther 60 ml of pyridine were added and the mixture was stirred underreflux for a further 1 h. The reaction mixture was treated with stirringwith 500 ml of ice and 110 ml of conc. hydrochloric acid. After additionwas complete, the mixture was stirred for a further 20 min, and theproduct was filtered off with suction, washed with water andrecrystallized from isopropanol. Yield: 12.85 g (62%).

¹H-NMR (200 MHz, d⁶-DMSO): δ=3.75 (s, 3H, OCH₃); 6.76 (d, J=15Hz, 1H,CHCOOCH₃); 7.73 (d, J=15Hz, 1H, Ar—CH); 7.84 (d, J=9Hz, 2H, Ar—H); 7.98(d, J=9Hz, 2H, Ar—H); 13.11 (s, broad, 1H, COOH). MS (Cl⁺): m/e=207.2(M+H⁺, 100%). HPLC: RP18, Nucleosil 300-5-C18, 250×4 mm; buffer A: H₂O,0.1% trifluoroacetic acid (TFA); buffer B: acetonitrile (80% v/v)/H₂ O(20% v/v), 0.1% TFA; gradient: first 5 min 90% buffer A/10% buffer B,then during 20 min to 90% buffer B, then 5 min 90% buffer B; flow rate 1ml/min; Rt32 18.05 min.

b) 4-(2-Methoxycarbonylethyl)benzoic Acid

8 g (38.8 mmol) of 4-(2-methoxycarbonylvinyl)benzoic acid were suspendedin 250 ml of dioxane and hydrogenated for 7 h at room temperature overPd/C (10% strength) at 1 bar of hydrogen. The mixture was filtered andthe solvent was removed in vacuo. Yield: 8.05 g (100%).

1H-NMR (200 MHz, d₆-DMSO): δ=2.67 (t, J=8Hz, 2H, CH ₂—COOCH₃); 2.93 (t,J=8Hz, 2H, Ar—CH ₂); 3.59 (s, 3H, OCH₃); 7.35 (d, 2H, Ar—H); 7.86 (d,J=9Hz, 2H, Ar—H); 12.80 (s, broad, 1H, COOH). MS (Cl⁺): m/e=209.2 (M+H⁺,100%). HPLC:RP18, Nucleosil 300-5-C18, 250×4 mm; buffer A: H₂O, 0.1%TFA; buffer B: acetonitrile (80% v/v)/H₂O (20% v/v), 0.1% TFA; gradient:first 5 min 90% buffer A, 10% buffer B, then during 20 min to 90% bufferB, then 5 min 90 % buffer B; flow rate 1ml/min; R_(t)=17.03 min.

c) tert-Butyl(2S)-2-Benzyloxycarbonylamino-3-(4-(2-methoxycarbonylethyl)benzoylamino)propionate

354 mg (1.7 mmol) of 4-(2-methoxycarbonylethyl)benzoic acid and 500 mg(1.7 mmol) of tert-butyl (2S)-3-amino-2-benzyloxycarbonylaminopropionatewere dissolved in 3 ml of dimethylformamide and treated with 557 mg (1.7mmol) ofO-((cyano-(ethoxycarbonyl)-methylidene)amino)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TOTU) and 204 mg (1.7 mmol) of diisopropylethylamineand the mixture was stirred at room temperature for 7 h at pH 7-8. Thesolvent was removed in vacuo, the residue was dissolved in ethyl acetateand the solution was washed three times each with KHSO₄ solution andNaHCO₃ solution until neutral. The organic phase was separated off anddried and the solvent was removed by distillation in vacuo. Yield: 770mg (93%).

MS (ES⁺): m/e=485.2 (M+H⁺, 100%).

d) tert-Butyl(2S)-2-Benzyloxycarbonylamino-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionate1.25 g (9.2 mmol) of 2-amino-1,4,5,6-tetrahydropyrimidine hydrochlorideand 1.03 g (9.2 mmol) of potassium tert-butoxide were dissolved in 3 mlof absolute dimethyl-formamide and stirred at room temperature for 30min. 740 mg (1.53 mmol) of tert-butyl(2S)-2-benzyloxycarbonylamino-3,4-(2-methoxycarbonylethyl)benzoylamino)propionatein 1 ml of dimethylformamide were then added and the mixture was stirredat room temperature for 4 h. The pH was adjusted to 4 using glacialacetic acid, the solvent was removed in vacuo and the residue waschromatographed on silica gel using dichloromethane/methanol/glacialacetic acid/water (9/110.110.1). Yield: 190 mg (38%).

MS (ES⁺): m/e=552.3 (M+H⁺, 100%).

e) (2S)-2-Benzyloxycarbonylamino-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionic Acid

1 90 mg (0.034 mmol) of tert-butyl(2S)-2-benzyloxycarbonylaminod-3-(4(2(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethy)benzoylamino)propionatewere dissolved in 5 ml of 95% strength trifluoroactic acid and stirredat room temperature for 1 h. The trifluoroacetic acid was removed bydistillation in vacuo and coevaporated with toluene, and the residue wasdissolved in glacial acetic acid, diluted with water and freeze-dried.Yield: 170 mg (1.00%).

MS (ES⁺): m/e=496.3 (M+H⁺, 100%)

Example 3 (2S)-2-Benzyloxycarbonylamino-3-(4-((1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)methyloxy)benzoylamino)propionicAcid

a) Benzyl 4-(Methoxycarbonylmethyloxy)benzoate

4.5 g (0.02 mol) of benzyl p-hydroxybenzoate were suspended in about 60ml of acetone together with 9.7 g (0.03 mol) of cesium carbonate andtreated with 2.3 ml (0.025 mol) of ethyl bromoacetate. The mixture wasthen refluxed until reaction was complete. For working-up, the reactionsolution was filtered through a clarifying layer and the filtrate wasconcentrated to dryness. The residue was taken up in ethyl acetate andthe mixture was washed three times each with 10% strength citric acidsolution and saturated NaCl solution. The organic phase was dried oversodium sulfate, filtered and concentrated. The residue wasrecrystallized from diisopropyl ether/heptane. Yield: 5.5 g.

b) 4-(Methoxycarbonylmethyloxy)benzoic Acid

5 g of benzyl 4-(methoxycarbonylmethyloxy)benzoate were dissolved inmethanol/ethyl acetate and hydrogenated in the presence of 600 mg ofcatalyst (Pd/C, 10% strength). After flushing with inert gas, thecatalyst was filtered off and the filtrate was concentrated in vacuo.The residue was triturated with diisopropyl ether/heptane (9/1) andfiltered off with suction. Yield: 3.3 g.

c) tert-Butyl(2S)-2-(Benzyloxycarbonylamino)-3-(4-(methoxycarbonylmethyloxy)benzoylamino)propionate

420 mg (0.002 mol) of 4-(methoxycarbonylmethyloxy)benzoic acid, 270 mg(0.002 mol) of 1-hydroxybenzotriazole and 588 mg (0.002 mol) oftert-butyl (2S)-3-amino-2-benzyloxycarbonylaminopropionate weredissolved in 5 ml of dimethylformamide. The solution was cooled to 0° C.and treated with 453 mg (0.0022 mol) of N,N′-dicyclohexylcarbodiimideand then stirred at 0° C. for 10 min and at room temperature for 2 h.For working-up, the urea was filtered off and the filtrate wasconcentrated to dryness. The pure compound was obtained bychromatography of the crude product on silica gel(dichloromethane/acetonitrile 20/1). Yield: 820 mg.

d) tert-Butyl(2S)-2-Benzyloxycarbonylamino-3-(4-((1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)methyloxy)benzoylamino)propionate

438 mg of tert-butyl(2S)-2-(benzyloxycarbonylamino)-3-(4-(methoxycarbonylmethyloxy)benzoylamino)propionate,606 mg of potassium tert-butoxide and 732 mg of2-amino-1,4,5,6-tetrahydropyrimidine hydrochloride were dissolved in 10ml of absolute dimethylformamide, and the solution was stirred at roomtemperature for 14 h and then concentrated to dryness in vacuo.

The residue was dissolved in ethyl acetate and the solution wasextracted with water. The organic phase was dried and concentrated invacuo, and the crude product was purified by chromatography on silicagel (dichloromethane/methanol 100/7.5). Yield: 370 mg.

e) (2S)-2-Benzyloxycarbonylamino-3-(4-((1,4,5,6-tetrahydropyrimidin-2ylcarbamoyl)methyloxy)benzoylamino)propionicAcid

87 mg of the tert-butyl ester obtained in step d) were stirred at roomtemperature for 15 min in 2 ml of 95% strength trifluoroacetic acid.After concentrating in vacuo, the mixture was triturated with ether, andthe residue was filtered off and dried. Yield: 79 mg.

MS (ES⁺): m/e=498.2 (M+H)⁺.

Example 4 Isopropyl (2S)-2-Benzyloxycarbonylamino-3-(4-(3-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)propyloxy)phenyl)propionateHydrochloride

23.88 g (0.04 mol) of the compound of Example 1 (as trifluoroacetic acidsalt) were suspended in 400 ml of isopropanol. To this suspension wasadded at −15° C. under an inert gas atmosphere a previously preparedsolution of thionyl chloride in isopropanol (for the preparation of thissolution 10.4 ml of thionyl chloride had been added dropwise at −10 to−15° C. and unter an inert gas atmosphere within 5 min to 160 ml ofisopropanol and the mixture had been stirred at −10° C. for further 20min). After completion of the addition the temperature rose within 30min to room temperature. Then, the meanwhile clear solution was heatedat 60° C. under stirring for 7 hours. Stirring was continued withoutheating overnight. By TLC control, the reaction exhibited to becompleted. Solvents were removed by rotary destination in vacuo. Theresidue was suspended in 100 ml of isopropanol and the isopropanol wasremoved in vacuo. The solid residue was triturated with diethylether andseparated by suction filtration. The raw product was suspended in 120 mlof isopropanol, heated to reflux with 2.4 g of charcoal and filtered.After cooling, the colourless product was separated by filtration.Yield: 16.2 g of an off-white solid.

MS (ES⁺): m/e=525 (M+H⁺, 100%). Elemental analysis: calc. C 59.9% H 6.6%N 10.0% Cl 6.3%; found C 59.3% H 6.7% N 10.0% Cl 6.6%; ¹H-NMR (200 MHz,d₆-DMSO): δ=1.1 (dd, 6H, J=7Hz), 1.8, 1.95 and 2.5 (m, each 2H), 2.85(m, 2H), 3.35 (t, 4H, J=3-4Hz), 3.95 (t, 2H, J=3-4Hz), 4.15 (m, 1H), 4.9(sep, 1H, J=7Hz), 5.0 (s, 2H,), 6.9 and 7.1 (d, each 2H, J=7Hz), 7.3 (m,5H), 7.7 (d, 1H, J=7Hz).

Example 5 Ethyl(2S)-2-Benzyloxycarbonylamino-3-(4-(3-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)propyloxy)phenyl)propionateHydrochloride

0.14 ml (1.15 eq.) of thionyl chloride were added at −10° C. to 5 ml ofethanol and stirred for 10 min at this temperature. Then 1 g (1.66 mmol)of the compound of Example 1 were added as a suspension in 10 ml ofethanol. Under stirring, the mixture was warmed to room temperature andstirred for further 5 hours. The solution which had meanwhile becomeclear, was evaporated in vacuo, the residue was dissolved in water and,after filtration, subjected to lyophilization. Yield: 0.85 g of acolourless, amorphous solid. MS (ES⁺): m/e=511 (M+H⁺, 100%).

Example 6

(2S)-2-Benzyloxycarbonylamino-3-(4-(3-(4,5-dihydro-1H-imidazol-2-ylcarbamoyl)propyloxy)phenyl)propionicAcid

a) tert-Butyl(2S)-2-Benzyloxycarbonylamino-3(4-(3-(4,5-dihydro-1H-imidazol-2-ylcarbamoyl)propyloxy)phenyl)propionate

340 mg of 4,5-dihydro-1H-imidazol-2-ylamine, 13.6 mg of imidazole and26.8 mg of lithium iodide were added to a solution of 970 mg oftert-butyl(2S)-2-benzyloxycarbonylamino-3-(4-(3-ethoxycarbonylpropyloxy)phenyl)propionate(Example 1a) in 5 ml of absolute dimethylformamide. The solution wasstirred at 40° C. for 4 hours, an additional 170 mg of4,5-dihydro-1H-imidazol-2-ylamine were added and the solution stirred at55° C. for further 3 hours. After removal of the solvent in vacuo, theresidue was treated with ethyl acetate, filtered, extracted with 10%strength aqueous KHCO₃ solution, dried over MgSO₄, filtered,concentrated in vacuo and precipitated with diisopropyl ether. The crudeproduct was purified by silica gel chromatography(dichloromethane/methanol/glacial acetic acid 90/10/1). 250 mg of anamorphous product were obtained.

MS (ES⁺): m/e=525.2 (M+H, 100%).

b)(2S)-2-Benzyloxycarbonylamino-3-(4-(3-(4,5-dihydro-1H-imidazol-2-ylcarbamoyl)propyloxy)phenyl)propionicAcid

200 mg of tert-butyl(2S)-2-benzyloxycarbonylamino-3-(4-(3-(4,5-dihydro-1H-imidazol-2-ylcarbamoyl)-propoxy)phenyl)propionatewere dissolved in 5 ml of trifluoroacetic acid/water (95/5) and thesolution was stirred at room temperature for 15 min. The reactionsolution was then concentrated in vacuo. The residue was dissolved inwater and the solution was freeze-dried. Yield: 100%.

MS (ES⁺): m/e=469.2 (M+H⁺, 100%).

Pharmacological Testing

The inhibition of bone resorption by the compounds according to theinvention can be determined, for example, with the aid of an osteoclastresorption test (“PIT ASSAY”), for example analogously toWO-A-95/132710.

The inhibitory action of the compounds according to the inventionagainst the vitronectin receptor α_(v)β₃ can be determined, for example,as described below.

Test for the measurement of the inhibition of binding of 293 cells tohuman vitronectin (Vn/293 cell test)

1. Purification of Human Vitronectin

Human vitronectin is isolated from human plasma and purified by affinitychromatography according to the method of Yatohyo et al., Cell Structureand Function, 1988, 23, 281-292.

2. Cell Test

293 cells, a human embryonic kidney cell line, which are cotransfectedwith DNA sequences for the α_(v) and β₃ subunits of the vitronectinreceptor α_(v)β₃ , are selected for a high rate of expression (>500,000α_(v)β₃ receptors/cell) according to the FACS method. The selected cellsare cultured and sorted again by means of FACS in order to obtain astable cell line (15 D) with expression rates >1,000,000 copies ofα_(v)β₃ per cell.

A Linbro 96-well tissue culture plate with a flat bottom is coatedovernight at 4° C. with human vitronectin (0.01 mg/ml, 0.05 ml/well) inphosphate-buffered saline solution (PBS) and then blocked with 0.5%strength BSA (bovine serum albumin). Solutions of the test substancesfrom 10⁻¹⁰ mol/l to 2×10⁻³ mol/l in glucose-containing DMEM medium areprepared and 0.05 ml/well of the solution are added to the plate in eachcase. The cells which express high levels of α_(v)β₃ (for example 15 D)are suspended in glucose-containing DMEM medium and the suspension isadjusted to a content of 25,000 cells/0.05 ml of medium. 0.05 ml of thiscell suspension is added to each well and the plate is incubated at 37°C. for 90 min. The plate is washed three times with warm PBS in order toremove unbound cells. The bound cells are lyzed in citrate buffer (25mM, pH 5.0) which contains 0.25% Triton X-100. The hexoseamidasesubstrate p-nitrophenyl-N-acetyl-β-D-glucosaminide is then added and theplate is incubated at 37° C. for 90 min. The reaction is stopped with aglycine (50 mM)/EDTA (5 mM) buffer (pH 10.4) and the absorption of eachwell is measured at 405-650 nm. The data are analyzed according tostandard processes.

The following test results were obtained:

Vn/293 cell test Compound IC₅₀ (μM) Example 1 0.028 Example 2 0.017Example 3 1.35 Example 6 0.032

What is claimed is:
 1. A compound of formula I

in which: R¹ and R² together are a saturated or unsaturated bivalent(C₂-C₉)-alkylene radical and thereby form a ring, which is unsubstitutedor is substituted by one or more groups selected from the groupconsisting of halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₆)-alkyl-, (C₅-C₁₄)-heteroaryl,(C₅-C₁₄)-heteroaryl-(C₁-C₆)-alkyl-, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₆)-alkyl- and oxo, where a 5-membered to7-membered saturated or unsaturated ring may be fused to adjacent carbonatoms of the (C₂-C₉) alkylene radical, thereby forming a bicyclicstructure and is unsubstituted or is substituted by R³, wherein said5-membered to 7-membered saturated or unsaturated ring is a carbocyclicring or a heterocyclic ring containing one or two nitrogen atoms; R³ is(C₁-C₈)-alkyl, (C₁-C₈)-alkoxy, (C₅-C₁₄)-aryl,(C₅-C₁₄)-aryl(C₁-C₄)-alkyl-, halogen, trifluoromethyl, hydroxyl, nitro,or amino; R⁴ is hydrogen, (C₁-C₆)-alkyl-CO—O—(C₁-C₄)-alkyl- or(C₁-C₆)-alkyl, which is unsubstituted or substituted by a radicalselected from the group consisting of hydroxyl, (C₁-C₄)-alkoxy,(C₁-C₄)-alkyl-S(O)₂—, NR⁷R^(7′) and N⁺R⁷, R^(7′)R^(7″)Q³¹ , wherein R⁷,R^(7′)and R^(7″)independently of one another are hydrogen,(C₁-C₆)-alkyl, (C₅-C₁₄)-aryl or (C₅-C₁₄)-aryl-(C₁-C₆)-alkyl- and Q⁻ is aphysiologically tolerable anion,  or in which R⁴ is one of the radicals

in which the bonds, via which the radicals are bonded, are indicated bydashed lines; R⁵ is (C₁-C₆)-alkyl, (C₆-C₁₄)-aryl-(C₁-C₆)-alkyl- or(C₅-C₁₄)-heteroaryl-(C₁-C₆)-alkyl-, where the aryl radical or theheteroaryl radical is unsubstituted or is substituted by one, two orthree radicals R³; R⁶ is hydrogen, (C₁-C₆)-alkyl-O—CO—, hydroxyl,(C₁-C₆)-alkyl-O—CO—O— or nitro; A is CH2, O, S or NH; m is 1, 2or 3; nis 0 or 1; in all its stereoisomeric forms and mixtures thereof in allratios, or its physiologically tolerable salt.
 2. A compound of theformula I as claimed in claim 1, in which R¹ and R² together are asaturated or unsaturated bivalent (C₂-C₅)-alkylene radical, where the(C₂-C₅)-alkylene radical is unsubstituted or is substituted by a radicalfrom the group consisting of halogen, (C₁-₆)-alkyl, (C₁-C₆)-alkoxy,(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₆)-alkyl-, (C₅-C₄)-heteroaryl,(C₅-C₁₄)-heteroaryl-(C₁-C₅)-alkyl-, (C₃-O₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₆)-alkyl- and oxo, and where a 5-membered to7-membered saturated or unsaturated ring which is unsubstituted orsubstituted by R³, and which is a carbocyclic ring or heterocyclic ringcontaining one or two ring nitrogen atoms, can be fused to acarbon-carbon bond in the (C₂-C₅)-alkylene radical; R³ is (C_(1-C)₄)-alkyl or (C₁-C₄)-alkoxy; R⁴ is hydrogen or (C₁-C₆)-alkyl which isunsubstituted or is substituted by a radical from the group consistingof (C₁-C₄)-alkoxy, C₁-C₄)-alkyl-S(O)₂— and NR⁷R′, where R⁷ andR^(′)independently of one another are hydrogen or (C₁-C₄)-alkyl; R⁵ is(C₁-C₈)-alkyl or a radical of the formula II

 in which q is 0 or 1 and the radical R³ can be located in any desiredposition of the phenyl radical; R⁶ is hydrogen or (C₁-C₆)-alkyl-O—CO—; Ais CH₂ or O; m is 1, 2or 3; n is 0 or 1; in all its stereoisoeric formsand mixtures thereof in all ratios, or its physiologically tolerablesalt.
 3. A compound of the formula I as claimed in claim 1 or 2, inwhich R¹ and R² together are a saturated or unsaturated bivalent(C₂-C₄)-alkylene radical, where the (C₂-C₄)-alkylene radical isunsubstituted or is substituted by a radical from the group consistingof halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₆)-alkyl-, (C₅-C₁₄)-heteroaryl,(C₅-C₁₄)-heteroaryl-(C₁-C₆)-alkyl-, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₆)-alkyl- and oxo, and where a 5-membered to7-membered saturated or unsaturated ring which is unsubstituted or issubstituted by R³, and which is a carbocyclic ring or heterocyclic ringcontaining one or two ring nitrogen atoms, can be fused to acarbon-carbon bond in the (C₂-C₄)-alkylene radical; R³ is (C₁-C₄)-alkylor (C₁-C₄)-alkoxy; R⁴ is hydrogen or (C₁-C₆)-alkyl; R⁵ is (C₁-C₄)-alkylor a radical of the formula II

 in which q is 0 or 1 and the radical R³ can be located in any desiredposition of the phenyl radical; R⁶ is hydrogen or (C₁-C₄)-alkyl-O—CO—; Ais CH₂ or O; m is 1, 2 or 3; n is 0 or 1; in all its stereoisomericforms and mixtures thereof in all ratios, or its physiologicallytolerable salt.
 4. A compound of the formula I as claimed in one or moreof claims 1 to 3, in which R¹ and R² together are a saturated orunsaturated bivalent (C₂-C₃)-alkylene radical, where the(C₂-C₃)-alkylene radical is unsubstituted or is substituted by a radicalfrom the group consisting of halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₆)-alkyl-, (C₅-C₁₄)-heteroaryl,(C₅-C₁₄)-heteroaryl-(C₁-C₆)-alkyl-,(C₃-C₁₂)-cycloalkyl(₃-C₁₂)-cycloalkyl-(C₁-C₆)-alkyl- and oxo, and wherea 5-membered to 7-membered saturated or unsaturated ring which isunsubstituted or is substituted by R³, and which is a carbocyclic ringor heterocyclic ring containing one or two ring nitrogen atoms, can befused to a carbon-carbon bond in the (C₂-C₃)-alkylene radical; R³ is(C₁-C₄)-alkyl or (C₁-C₄)-alkoxy; R⁴ is hydrogen or (C₁-C₄)-alkyl; R⁵ is(C₁-C₄)-alkyl or a radical of the formula II

 in which q is 0 or 1 and the radical R³ can be located in any desiredposition of the phenyl radical; R⁶ is hydrogen or (C₁-C₄)-alkyl-O—CO—; Ais CH₂; m is 1; n is 1; in all its stereoisomeric forms and mixturesthereof in all ratios, or its physiologically tolerable salt.
 5. Acompound of the formula I as claimed in one or more of claims 1 to 3, inwhich R¹ and R² together are a saturated or unsaturated bivalent(C₂-C₃)-alkylene radical, where the (C₂-C₃)-alkylene radical isunsubstituted or is substituted by a radical from the group consistingof halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₆)-alkyl-, (C₅-C₁₄)-heteroaryl,(C₅-C₁₄)-heteroaryl-(C₁-C₆)-alkyl-, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₆)-alkyl- and oxo, and where a 5-membered to7-membered saturated or unsaturated ring which is unsubstituted or issubstituted by R³, and which is a carbocyclic ring or heterocyclic ringcontaining one or two ring nitrogen atoms, can be fused to acarbon-carbon bond in the (C₂-C₃)-alkylene radical; R³ is (C₁-C₄)-alkylor (C₁-C₄)-alkoxy; R⁴ is hydrogen or (C₁-C₄)-alkyl; R⁵ is (C₁-C₄)-alkylor a radical of the formula II

 in which q is 0 or 1 and the radical R³ can be located in any desiredposition of the phenyl radical; R⁶ is hydrogen or (C₁-C₄)-alkyl-O—CO—; Ais oxygen; m is 1; n is 1; in all its stereoisomeric forms and mixturesthereof in all ratios, or its physiologically tolerable salt.
 6. Acompound of the formula I as claimed in one or more of claims 1 to 3, inwhich R¹ and R² together are a saturated or unsaturated bivalent(C₂-C₃)-alkylene radical, where the (C₂-C₃)-alkylene radical isunsubstituted or is substituted by a radical from the group consistingof halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₆)-alkyl-, (C₅-C₁₄)-heteroaryl,(C₅-C₁₄)-heteroaryl-(C₁-C₆)-alkyl-, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₆)-alkyl- and oxo, and where a 5-membered to7-membered saturated or unsaturated ring which is unsubstituted or issubstituted by R³, and which is a carbocyclic or heterocyclic ringcontaining one or two ring nitrogen atoms, can be fused to acarbon-carbon bond in the (C₂-C₃)-alkylene radical; R³ is (C₁-C₄)-alkylor (C₁-C₄)-alkoxy; R⁴ is hydrogen or (C₁-C₄)-alkyl; R⁵ is (C₁-C₄)-alkylor a radical of the formula II

 in which q is 0 or 1 and the radical R³ can be located in any desiredposition of the phenyl radical; R⁶ is hydrogen or (C₁-C₄)-alkyl-O—CO—; Ais oxygen; m is 3; n is 0; in all its stereoisomeric forms and mixturesthereof in all ratios, or its physiologically tolerable salt.
 7. Acompound of the formula I as claimed in one or more of claims 1 to 6, inwhich R⁵ is the unsubstituted benzyl radical, in all its stereoisomericforms and mixtures thereof in all ratios, or its physiologicallytolerable salt.
 8. A compound of the formula I as claimed in one or moreof claims 1 to 7, in which R¹ and R² together are a saturated bivalent(C₂-C₃)-alkylene radical which is unsubstituted; R⁴ is hydrogen or(C₁-C₄)-alkyl; R⁵ is unsubstituted benzyl; R⁶ is hydrogen; A is oxygen;m is 3; n is 0; in all their stereoisomeric forms and mixtures thereofin all ratios, or their physiologically tolerable salt. 9.(2S)-2-Benzyloxycarbonylamino-3-(4-(3-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)propyloxy)phenyl)propionicacid or its physiologically tolerable salt. 10.(2S)-2-Benzyloxycarbonylamino-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionicacid or its physiologically tolerable salt. 11.(2S)-2-Benzyloxycarbonylamino-3-(4-((1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)methyloxy)benzoylamino)propionicacid or its physiologically tolerable salt. 12.(2S)-2-Benzyloxycarbonylamino-3-(4-(3-(4,5-dihydro-1H-imidazol-2-ylcarbamoyl)propyloxy)phenyl)propionicacid or its physiologically tolerable salt.
 13. A process for thepreparation of a compound of the formula I as claimed in one or more ofclaims 1 to 12 which comprises linking two or more fragments which canbe derived retrosynthetically from the formula I.
 14. The process asclaimed in claim 13, wherein a carboxylic acid or a carboxylic acidderivative of the formula III

in which R⁴, R⁵, A, n and m are defined as indicated in claims 1 to 12,or alternatively functional groups can be present in the form ofprecursors or in protected form, and X is a nucleophilicallysubstitutable leaving group, is reacted with a guanidine or guanidinederivative of the formula IV

in which R¹, R² and R⁶ are defined as indicated in claims 1 to 12, oralternatively functional groups can be present in the form of precursorsor in protected form.
 15. A pharmaceutical composition, comprising atleast one compound of the formula I as claimed in one of claims 1 to 12or its physiologically tolerable salt together with a pharmaceuticallyinnocuous carrier.
 16. A method of inhibiting a vitronectin receptorcomprising contacting said vitronectin receptor with an inhibitoryamount of a compound of formula I as claimed in one of claims 1 to 12.17. A method for inhibiting bone resorption comprising administering toa patient in need thereof an inhibitory amount of a compound of formulaI as claimed in one of claims 1 to 12 or its physiologically tolerablesalt.
 18. A method of treating osteoporosis comprising administering toa patient in need thereof an effective amount of a compound of formula Ias claimed in one of claims 1 to 12 or its physiologically tolerablesalt.
 19. A method of treating tumor growth or tumor metastasiscomprising administering to a patient in need thereof an effectiveamount of a compound of formula I as claimed in one of claims 1 to 12 orits physiologically tolerable salt.
 20. A method of treatingcardiovascular disorders, restenosis, arteriosclerosis, nephropathies orretinopathies comprising administering to a patient in need thereof aneffective amount of a compound of formula I as claimed in one of claims1 to 12 or its physiologically tolerable salt.